Currently there are few strategies for detecting and mitigating Alzheimer's disease (AD) early in the disease process. Converging evidence suggests a promising role for sleep in detection and intervention. Obstructive sleep apnea (OSA) is significantly more prevalent in dementia than in the general population and animal and human studies suggest that OSA and sleep disruption may promote the formation of amyloid (A) plaques in the brain, a hallmark of AD pathology. Thus, sleep disturbance may be a modifiable risk factor for AD, for which treatments are already available. However, human studies investigating the role of sleep disruption in AD have relied on behavioral sleep measures and have not measured brain function. Amyloid plaques disrupt neural signaling, which may manifest as regional EEG abnormalities. Therefore sleep electroencephalography (EEG) may be a powerful tool for detecting very early biomarkers of neuropathology. This hypothesis is based on our group's findings of a EEG deficits in amnestic Mild Cognitive Impairment. Sleep EEG is particularly sensitive to brain network function as it is immune to the attentional fluctuations that affect waking EEG. The objective of this proposal is to determine which aspects of sleep are associated with amyloid pathology in an asymptomatic population at risk for AD, and whether brain change in preclinical AD is detectable by sleep EEG. Our Central Hypothesis is that sleep disturbance increases vulnerability to amyloid pathology, detectable by sleep EEG. This proposal is integrated with a longitudinal study of 100 asymptomatic middle-aged adults enriched for risk of AD (Project 2 of the Wisconsin ADRC P50 AG033514) in which CSF, MRI, cognitive tests and genotype are being collected. We will test our hypothesis with two specific aims: Aim 1: Identify sleep characteristics that are associated with midlife beta amyloid deposition. To accomplish this aim we will conduct home sleep studies in 100 adults at risk for AD, and correlate sleep fragmentation and OSA severity with amyloid levels in cerebrospinal fluid (CSF A42). Aim 2: Determine whether sleep EEG topography is altered in preclinical AD. We will perform hdEEG sleep studies (n=100) in adults with and without a family history (FH) of AD, which we have shown is associated with signs of preclinical AD. We predict that the effect on FH on EEG will be greater in more severe OSA. This research could have significant translational impact by uncovering targets for future studies of sleep-based interventions, disease markers and testable hypotheses of AD mechanisms. The plan builds on the applicant's experience in sleep research with training in AD neurobiology, EEG and actigraphy, and is supported by the extensive resources of Wisconsin Sleep and the Wisconsin Alzheimer's Disease Research Center.